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Abstract Background Rodents are considered to contribute strongly to the risk of tick-borne diseases by feeding Ixodes ricinus larvae and by acting as amplifying hosts for pathogens. Here, we tested to what extent these two processes depend on rodent density, and for which pathogen species rodents synergistically contribute to the local disease risk, i.e. the density of infected nymphs (DIN). Methods In a natural woodland, we manipulated rodent densities in plots of 2500 m2 by either supplementing a critical food source (acorns) or by removing rodents during two years. Untreated plots were used as controls. Collected nymphs and rodent ear biopsies were tested for the presence of seven tick-borne microorganisms. Linear models were used to capture associations between rodents, nymphs, and pathogens. Results Investigation of data from all plots, irrespective of the treatment, revealed a strong positive association between rodent density and nymphal density, nymphal infection prevalence (NIP) with Borrelia afzelii and Neoehrlichia mikurensis, and hence DIN’s of these pathogens in the following year. The NIP, but not the DIN, of the bird-associated Borrelia garinii, decreased with increasing rodent density. The NIPs of Borrelia miyamotoi and Rickettsia helvetica were independent of rodent density, and increasing rodent density moderately increased the DINs. In addition, NIPs of Babesia microti and Spiroplasma ixodetis decreased with increasing rodent density, which had a non-linear association with DINs of these microorganisms. Conclusions A positive density dependence for all rodent- and tick-associated tick-borne pathogens was found, despite the observation that some of them decreased in prevalence. The effects on the DINs were variable among microorganisms, more than likely due to contrasts in their biology (including transmission modes, host specificity and transmission efficiency). The strongest associations were found in rodent-associated pathogens that most heavily rely on horizontal transmission. Our results draw attention to the importance of considering transmission mode of a pathogen while developing preventative measures to successfully reduce the burden of disease.

Objective: To investigate the TrkA inhibitor, ASP7962, for treatment of painful knee osteoarthritis., Design: Phase 2a, double-blind, placebo- and naproxen-controlled, double-dummy, parallel-group study. Adults with knee osteoarthritis were randomized (2:2:1) to ASP7962 (100 mg), placebo, or naproxen (500 mg) twice daily (BID) for 4 weeks. Primary endpoint: change from baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale score. Secondary endpoints: change from baseline to Weeks 1, 2, and End of Treatment (EoT) in WOMAC pain subscale score; change from baseline to Weeks 1, 2, 4, and EoT in WOMAC physical function and stiffness subscales, walking pain and WOMAC total scores; and change from baseline in daily average pain score., Results: 215 participants were randomized (ASP7962 100 mg BID, n = 85; placebo, n = 87; naproxen 500 mg BID, n = 43). No significant difference was observed between ASP7962 and placebo in change from baseline to Week 4 in WOMAC pain subscale score (-0.14; 90% 2-sided CI: -0.62, 0.34; P = 0.316); a significant difference was observed between naproxen and placebo (-0.67; 80% 2-sided CI: -1.12, -0.23; P = 0.027). No differences were observed between ASP7962 and placebo in change from baseline in any WOMAC subscale score; statistically significant changes were observed between naproxen and placebo (P ≤ 0.01, all time points for all WOMAC endpoints). ASP7962 was safe and well-tolerated., Conclusions: Four-week treatment with ASP7962 (100 mg BID) did not improve pain or physical function in individuals with painful knee osteoarthritis. ClinicalTrials.gov, NCT02611466; EudraCT Number, 2014-004996-22., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Only small amounts of data are available on the prescription frequency of physical therapies (PT) for patients with rheumatoid arthritis (RA)., Objective: The aim of the study was to evaluate prescription frequencies of PT considering functional status and sociodemographic factors., Material and Methods: A total of 98,963 adults diagnosed with RA in 2013 were identified in claims data from the BARMER health insurance. A questionnaire was sent to a representative sample of 6193 people requesting information on the disease status. Of these 2535 persons were included who agreed to the linking of the questionnaire and claims data and who confirmed a diagnosis of RA. From the routine claims data the prescription of PT and occupational therapy as well as the medical discipline of the prescribing physician were analyzed. Multivariable logistic regression was conducted to determine which variables (age, sex, M05/M06 diagnosis, residential area, income, functional status and rheumatological care) were associated with the use of PT., Results: In 2015 a total of 47% of the study population received PT (35% physiotherapy, 15% thermotherapy, 15% manual therapy, 2% electrotherapy and 6% massage) and 3% occupational therapy. Of the PT prescriptions 37% were issued by general practitioners, 27% by orthopedists and 18% by rheumatologists. Women and persons living in the eastern states of Germany and patients with high functional impairment were prescribed PT more often. Income, educational status, seropositivity and rheumatological care did not have any influence on the frequency of prescription of PT., Conclusion: There are deficits in the outpatient prescription of PT but without indications of an undersupply of population groups due to low socioeconomic status. In contrast to the prescription of disease-modifying antirheumatic drug (DMARD) treatment, PT is predominantly prescribed by general practitioners.

Background: The aim of this stud was to assess clinical outcomes after implantation of a hydrophobic toric intraocular lens (IOL) in patients undergoing cataract surgery., Patients and Methods: 22 eyes (16 patients) with at least 0.8 diopter (D) of corneal astigmatism having routine cataract surgery were included. After marking the final axis of the IOL, phacoemulsification, implantation and alignment of a toric IOL was performed. Uncorrected distance visual acuity (UDVA), best corrected distance visual acuity (BDVA), manifest refraction, and keratometry were measured 5 to 19 months postoperatively. Individual patient satisfaction was also recorded. The cylinder axis of the toric IOL was determined at a slitlamp examination., Results: The mean UDVA postoperatively was 0.3 logMAR±0.23 (SD) and was 0.3 logMAR or better in 63.6% of eyes. The mean refractive cylinder decreased significantly postoperatively, ranging from -3.3±1.5 D to -1.3±0.7 D. The mean absolute IOL misalignment was 7.5 degrees (range 0 to 21°). The good UDVA resulted in high levels of patient satisfaction., Conclusions: Implantation of a toric IOL during cataract surgery was an effective and safe method to manage corneal astigmatism in this series of patients., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Osteopontin is an extracellular matrix protein with diverse immunomodulatory functions. The authors assessed the safety, tolerability, pharmacokinetics, pharmacodynamics and initial efficacy of the humanised monoclonal antibody ASK8007, which blocks osteopontin., Methods: In this double-blind, multicentre, combined first-in-man, single-dose escalation (phase I, part A) and proof-of-concept, multiple-dose (phase IIA, part B) study, rheumatoid arthritis (RA) patients with active disease were randomly assigned to receive ASK8007 or placebo intravenously. Safety monitoring, pharmacokinetic and pharmacodynamic analyses and clinical assessments were performed throughout the study. The expression of phenotypic cell markers was evaluated in synovial tissue biopsy samples obtained at baseline and 43 days after initiation of treatment (part B) by immunohistochemistry and digital image analysis. Two co-primary efficacy endpoints were the change from baseline in the disease activity score evaluated in 28 joints (DAS28) and the change from baseline in the number of CD68 synovial sublining macrophages, both assessed on day 43 (part B)., Results: ASK8007 was overall safe and well tolerated up to the highest studied dose (20 mg/kg). Quantifiable concentrations of ASK8007 were detected in synovial fluid. No differences were observed for changes from baseline in DAS28 and CD68 sublining macrophages between ASK8007 and placebo-treated patients. Within the ASK8007 treatment group, there were also no apparent clinical responses or changes in sublining macrophages. In addition, ASK8007 treatment did not change other assessed biomarkers., Conclusions: Osteopontin blockade is well tolerated and not related to safety concerns. These results consistently show that osteopontin blockade is unlikely to induce robust clinical improvement in RA patients.

Despite its well-known cardiotoxicity, the anthracycline doxorubicin continues to be a widely used chemotherapeutic agent. The flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) has shown protection against doxorubicin-induced cardiotoxicity in mice. However, this protection has not been observed in humans. This prompted us to investigate monoHER metabolism in humans and compare it with that in mice. Five healthy volunteers received monoHER by intravenous infusion. After infusion, bile fluid was collected, and the monoHER metabolites were identified by liquid chromatography-diode-array detection (LC-DAD), time-of-flight mass spectrometry (TOF-MS), and (1)H-nuclear magnetic resonance (NMR). Thirteen different metabolites were identified. MonoHER was predominantly converted into inactive glucuronidated metabolites. In mice, the major metabolic route is methylation, which forms bioactive metabolites that are implicated in the cardioprotective effect of monoHER. This indicates that the different pharmacological effects of monoHER in mice and humans might be explained by a difference in monoHER metabolism. This study adds to the growing appreciation of flavonoid metabolites as bioactive compounds.

Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 μM and 0.37 μM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 μM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs., Methods: To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-κB (NF-κB) inactivation in the chemosensitising effect of monoHER., Results: MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-κB activation., Conclusion: These results suggest that reduction of doxorubicin-induced NF-κB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells.

Aims: We assessed to what extent fructans of different degrees of polymerization (DP) differ in their prebiotic effectiveness towards in vitro microbial communities from the proximal and distal colon., Methods and Results: Two short chain fructans - oligofructose (DP 2-20) and inulin (DP 3-60) - were administered to the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) at 2.5 g day(-1). The influence of fructan addition towards fermentation activity and microbial community composition from the different SHIME colon compartments were evaluated. Both fructans exerted prebiotic effects with significantly higher butyrate and propionate production and stimulation of lactic acid-producing bacteria. Compared with oligofructose, it was noted that it took more time before significant effects from inulin addition were observed. Yet, the higher short-chain fatty acid production and lower proteolytic activity showed that the prebiotic effects from inulin were more pronounced than oligofructose. Also, the bifidogenic effects from inulin vs oligofructose were higher in the distal colon compartments and this effect was prolonged in the distal colon once the addition was stopped., Conclusions: Inulin has more pronounced prebiotic effects than oligofructose towards both fermentation activity and bacterial community composition in the SHIME model., Significance and Impact of the Study: Its slower fermentation rate and higher prebiotic potency makes inulin a more interesting compound than oligofructose to beneficially influence the microbial community from both the proximal and distal colon regions.

We estimated and compared the action of three selected strains of bifidobacteria in a semi-synthetic medium for different degrees of polymerization of fructo-oligosaccharides contained in three commercial products derived from chicory inulin: Fibrulose F97 (shorter chains), Fibruline Instant (native chains), Fibruline LC (longer chains). Biomass and production of lactate and acetate were greater when the substrate contained mostly shorter chain fructo-oligosaccharides. Shorter chains were first to be consumed, and one strain could use longer chains. As the degree of polymerization increased, residual fructo-oligosaccharides increased after growth of the strains, and the rate of consumption of fructo-oligosaccharides decreased.

The metallic interstitial nitride Ni(3)N was prepared from Ni(NH(3))(6)Cl(2) and NaNH(2) in supercritical ammonia (p(NH(3)) approximately 2 kbar) at 523 K. Its previously reported crystal structure, as determined from X-ray powder data, was confirmed by neutron powder diffraction: Ni(3)N crystallizes in the hexagonal epsilon-Fe(3)N-type structure (P6(3)22, Z = 2, a = 4.6224 A and c = 4.3059 A at room temperature). The N atoms on the octahedral sites of an hcp arrangement of Ni show virtually complete occupational order at ambient temperatures, which is preserved up to its thermal decomposition at T approximately 600 K. This behavior is in marked contrast to that of the isotypic iron nitride, epsilon-Fe(3)N, which shows reversible partial disordering within the same range of temperatures. Possible reasons for the different behaviors of the two nitrides epsilon-Fe(3)N and Ni(3)N are discussed.

Monoclonal antibodies against glutamic acid decarboxylase (anti-GAD) were modified with poly(ethylene glycol) (PEG), and the resulting conjugates were characterized. Monoclonal anti-GAD antibodies were purified from ATCC HB184 hybridoma cells by either cell culture supernatant or ascites fluid from BALB/c mice. Polyclonal rabbit IgG antibodies were also used as a model protein. Polyclonal rabbit IgG or purified anti-GAD was modified by PEG (MW = 5000 or 20000 Da) through either the lysine residues or through the carbohydrate moiety. Lysine modification was performed in PBS (pH 7.4) or 0.1 M borate (pH 9.2) by adding a molar excess (5-80) of a succinimidyl activated propionic acid terminated mPEG (SPA-PEG) while stirring at room temperature. Carbohydrate modifications were performed in PBS (pH 6.2) by first oxidizing the antibody with sodium periodate followed by incubation with hydrazide-terminated PEG followed by reduction with sodium cyanoborohydride. The degree of modification was assessed by 1H NMR or TNBS (trinitrobenzenesulfonic acid). Circular dichroism (CD) spectra were obtained for lysine-modified rabbit IgG at various degrees of modification ranging from 5 to 60 PEG per antibody. Binding was assessed using an ELISA method with GAD or rabbit anti-mouse-IgG (H+L) coated plates. The TNBS and 1H NMR analysis of the modified antibody showed reasonably similar results from 5 to 60 PEG per antibody. The 1H NMR method showed greater sensitivity at low modifications (below 20:1) and was fairly linear up to about 60 PEG per antibody. The CD spectra of the polyclonal rabbit IgG showed only small differences at variously modified antibody. The binding affinity of anti-GAD is lower for all PEG modifications with respect to unmodified anti-GAD. Modifications at pH 7.4 show lower binding to GAD than modifications at pH 9.2. Binding to GAD or anti-mouse-IgG is decreased as the degree of modification is increased. Lysine modifications showed lower binding to GAD or anti-mouse-IgG than carbohydrate modifications. Binding to GAD or anti-mouse-IgG is lower for PEG20000-modified anti-GAD with respect to PEG5000-modified anti-GAD.

Background: An inverse association between cigarette smoking and the risk of idiopathic PD has been found in many epidemiologic studies. The therapeutic and possible neuroprotective effects of nicotine formulations on parkinsonian symptoms are controversial., Methods: In a 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and tolerability of transdermal nicotine patches as an add-on treatment for cardinal symptoms were evaluated in 32 nonsmoking patients with PD. After a 1-week run-in phase, patients were randomized to receive nicotine patches (containing 17.5 mg nicotine in the first and 35.0 mg nicotine in the second and third weeks) or identically appearing placebo patches. After this treatment, 3 weeks without patch application followed. The same blinded examiner assessed the patients with the Columbia University Rating Scale, the Webster scale, the Schwab-England scale, a timed walking test, with an instrumental test for fine motor skills and hand tremor, and with the Hamilton Depression Scale., Results: No significant drug effects between both groups were observed in any of the scores and quantitative tests. Side effects were mild and comparable in frequency between both groups., Conclusions: With the dosage and the period of treatment chosen, transdermal nicotine patches are not effective as an add-on treatment for symptoms of PD.

Dystonia is a movement disorder involving sustained muscle contractions and abnormal posturing with a strong hereditary predisposition and without a distinct neuropathology. In this study the TOR1A (DYT1) gene was screened for mutations in cases of early onset dystonia and early onset parkinsonism (EOP), which frequently presents with dystonic symptoms. In a screen of 40 patients, we identified three variations, none of which occurred in EOP patients. Two infrequent intronic single base pair (bp) changes of unknown consequences were found in a dystonia patient and the mother of an EOP patient. An 18-bp deletion (Phe323_Tyr328del) in the TOR1A gene was found in a patient with early onset dystonia and myoclonic features. This deletion would remove 6 amino acids close to the carboxy terminus, including a putative phosphorylation site of torsinA. This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.

This study examined whether a rat model of surgically-induced endometriosis that reduces fertility also evokes vaginal hyperalgesia along with changes in vaginal compliance. In nine rats trained to escape vaginal distention, percent escape responses to different volumes of vaginal distention were measured for 2.5 months before and after endometriosis or sham surgery. Vaginal pressures were also measured simultaneously to provide an estimate of vaginal compliance. Endometriosis (or sham) was induced by autotransplantation of small pieces of uterus (or fat) on mesenteric cascade arteries, abdomen, and ovary. Escape responses were significantly increased only in rats whose autotransplants had formed cysts. Vaginal pressures, however, remained unchanged. This vaginal hyperalgesia may involve a process of viscero-visceral referred hyperalgesia.

Extracts of the stems of Jatropha divaricata have yielded the two new diterpenes ent-3 beta,14 alpha-hydroxypimara-7,9(11),15-triene-12-one (3) and the rearranged pimarane ent-15(13-->8)abeo-8 beta(ethyl)pimarane (4), which appears to be a new skeletal type. The rare cleistanthane diterpenes spruceanol (1) and cleistanthol (2) were also obtained.

c-Myc is associated with cell growth and cycling in many tissues and its deregulated expression is causally implicated in cancer, particularly lymphomagenesis. However, the contribution of c-Myc to lymphocyte development is unresolved. We show here that the formation of normal lymphocytes by c-Myc-/- cells is selectively defective. c-Myc-/- cells are inefficient, in an age-dependent manner, at populating the thymus, and subsequent thymocyte maturation is ineffective: they fail to grow and proliferate normally at the late double-negative (DN) CD4-CD8- stage. Because N-Myc expression in thymocytes usually declines at the late DN stage, these results confirm that the nonredundant contributions of Myc family members to development are related to their distinct patterns of developmental gene expression.

How germinal center (GC) B cells diversify their rearranged immunoglobulin genes by somatic hypermutation is unknown. However, the GC-specific activation-induced cytidine deaminase has been identified as a key factor controlling two central GC-specific events: somatic hypermutation and class-switch recombination of immunoglobulin genes. This factor may function as a catalytic subunit of an RNA-editing complex or, more directly, on DNA as a deoxy-cytidine deaminase in the hypermutation domain and class-switch region. Deamination of deoxy-cytidines on both strands may result in staggered DNA double-strand breaks (DSBs) that, in the hypermutation domain, become processed by member(s) of newly identified error-prone DNA polymerases. Direct evidence for DSBs in hot-spots of hypermutating immunoglobulin genes has been provided, implicating DSBs as reaction intermediates of an error-prone DSB-repair pathway acting specifically in GC B cells. These recent findings are key to the identification of the hypermutation mechanism.

Tin nitrides (Sn3N4) prepared by the reaction of Sn-halides with KNH2 in liquid ammonia and a subsequent vacuum annealing procedure were investigated with transmission mode XAFS experiments. While the near edge data suggest the presence of a univalent Sn-compound with a valency close to +4, the analysis of the extended X-ray absorption fine structure proves the presence of two different local Sn sites in this crystal structure: While Sn(1) is surrounded by 4 nitrogen in a distance of 2.06 A, each Sn(2) ion is coordinated with 6 nitrogen at about 2.17 A radial distance.

Objectives: It has been hypothesized that the dopaminergic deficit of older patients with Parkinson's disease (PD) is associated with a reduction in the dopamine-dependent personality trait "novelty seeking". It is unknown whether this may also be found in younger patients with PD whose dopaminergic deficit is considered to be purely motor., Material and Methods: We interviewed 122 patients below 51 years of age and 122 age- and sex-matched healthy controls with regard to clinical and sociodemographic data. Both groups had to fill out the Tridimensional Personality Questionnaire (TPQ) of Cloninger. Neuropsychological testing of formal intelligence and depression was also applied., Results: "Novelty seeking" was not different between both groups. Patients were more often depressed than controls, explaining their difference in "harm avoidance" on the TPQ. "Persistence", a sub-scale of the third TPQ dimension "reward dependence", was significantly higher in patients. Neither sex, nor age, nor educational status were correlated with one of the three personality traits., Conclusions: The higher rate of depression explains our finding of more "harm avoidance" among young PD patients. According to a literature review the choice and performance of controls is crucial whether personality traits in PD patients may be assessed as abnormal.

The generation of a diverse antigen receptor repertoire is fundamental for the functionality of the adaptive immune system. While the V(D)J recombination process that generates the primary antigen receptor repertoire is understood in great detail, it is still unclear by which mechanism immunoglobulin (Ig) genes are further diversified by somatic hypermutation. Using mouse strains that carry a non-functional, pre-defined V(H)D(H)J(H) gene segment in their IgH locus we demonstrate DNA double-strand breaks (DSBs) in and around V(H)D(H)J(H) in B cells undergoing somatic hypermutation. The generation of these DSBs depends on transcriptional activity, and their distribution along the V(H)D(H)J(H) segment parallels that of point mutations in the hypermutation domain. Furthermore, similar to hot spots of somatic hypermutation, 50-60% of all DSBs occur preferentially at RGYW motifs. DSBs may transiently dissociate the Ig promoter from the intronic enhancer to block further transcription and to initiate an error-prone non-homologous DSB repair pathway. In accord with this model large deletions are frequently produced, along with point mutations, in a V(H)D(H)J(H) segment inserted together with its promoter into the IgH locus in inverted orientation. Our data suggest that DSBs are reaction intermediates of the mechanism underlying somatic hypermutation.

Objective: To evaluate the opinions and attitudes of young patients with Parkinson's disease (PD) towards possible presymptomatic and prenatal genetic testing for their illness., Background: With progress in understanding of the genetic component in the etiology of PD, presymptomatic genetic testing may become available in subgroups of patients., Methods: During a survey on sociodemographic and risk factors 111 PD patients (mean age 45 years: mean age at PD onset 36 years) were given a questionnaire with six items about possible presymptomatic and prenatal genetic testing., Results: Fifty-seven patients (5196) had knowledge about presymptomatic and prenatal testing. Eighty patients (72%) would take a presymptomatic test, if they had an autosomal dominant form of PD and if the test were available. The most Important reasons given for taking the test were planning of partnership (40%) and family (48%). When being identified as a carrier of a presumed "Parkinson gene", 78 patients (70%) would decide not to have children. Sixty-three patients (57%) would choose to have prenatal testing. Attitudes were largely independent of sociodemographic and disease variables., Conclusions: When addressed as hypothetical persons at genetic risk, young patients with PD support possible presymptomatic genetic testing and, to a lesser extent, prenatal testing. Attitudes and reasons to participate in such hypothetical testing do not grossly differ from those of at-risk persons in established single-gene autosomal dominant disorders of late onset.

The new ergostane steroid ergosta-5,24(24')-diene-3beta,4beta,22R-triol (1), a pregnane, (E)-volkendusin, characterised as the diacetate (3), cycloartanes 4-6 and protolimonoids 7-9 were obtained from the leaves and twigs of Trichilia reticulata.

Extracts of the fruit of Clusia havetiodes var. stenocarpa have yielded three new prenylated benzophenone derivatives, 28,29-epoxyplukenetione A (1), 33-hydroperoxyisoplukenetione C (2), and 15,16-dihydro-16-hydroperoxyplukenetione F (3), as well as four which have been previously described, plukenetiones C, F, and G and sampsonione G.

How rearranged immunoglobulin (Ig) genes are further diversified by somatic hypermutation is unknown. Using VDJ passenger Ig heavy chain (IgH) knockin mouse strains, we now demonstrate a high frequency of DNA double-strand breaks (DSBs) in the targeted VDJ passenger gene of germinal center (GC) B cells. These DSBs parallel the distribution of mutations in the targeted hypermutation domain and are found preferentially at RGYW motifs, the intrinsic hot spots of somatic hypermutation. The introduction of DSBs appears to depend on transcriptional activity. Thus, secondary diversification of rearranged V gene segments relates to an error-prone nonhomologous DSB repair system acting in B cells of the GC.

Answers from a multiple choice questionnaire on the opinions about public sexual attitudes, on emotion from personal sexual practice, on personal sexual function, and on general health perception were compared between 121 patients with Parkinson's disease (mean age 45 years) and 126 age and sex matched community derived controls. Patients were more dissatisfied with their present sexual functioning and relationship, and perceived their general health as poorer than the controls, whereas opinions about public sexual attitudes were only marginally different. No differences were found for sexual function. Further analysis showed that the perception of sexual functioning and general health in younger patients with Parkinson's disease is considerably influenced by depression and state of unemployment.

The mechanisms that govern differentiation of T cell precursors during intrathymic development bridge an interdisciplinary research field of immunology, oncology and developmental biology. Critical checkpoints controlling early thymic T cell development and homeostasis are set by the proper signaling function of the IL-7 receptor, c-Kit receptor, and the pre-T cell antigen receptor (pre-TCR). Given the intimate link between cell cycle control and differentiation in T cell development, proto-oncogenes and tumor suppressors participate as physiological effectors downstream of these receptors not only to influence the cell cycle but also to determine differentiation and survival. Gain- or loss-of-function mutations of these downstream effectors uncouples partially or completely T cell precursors from these checkpoints, providing a selective advantage and enabling aberrant development. These effectors can be identified by provirus tagging in normal mice and more readily by complementation tagging in mice with a predefined block in T cell differentiation.

The photooxidation of C2H5NH2, (C2H5)2NH, HOC2H4NH2, (HOC2H4)2NH and (HOC2H4)3N using TiO2 and Pt/TiO2 as photocatalysts has been investigated. A laboratory set up was designed and a study on the influence of the concentration of the photocatalyst, the pH-value and the structure of the amine performed. The photocatalytic process was optimized with respect to the concentrations of the model substances during degradation. The decrease of the amine concentrations was found to be maximum at a pH of 10. The time-dependence of the formation of cationic breakdown products, such as NH3/NH4 and short-chain alkyl- and alkanolamines was studied by analyses with single column ion chromatography. The experimental data show that the photodegradation follows a Langmuir-Hinshelwood kinetic. The mineralization of the model substances also was monitored by measurements of the decrease of the TOC and of the formation of NO2 and NO3. The different mineralization efficiencies for the model substances studied are discussed with regard to their structure and adsorption behaviour on the photocatalyst. A possible breakdown mechanism involving the electrophilic attack of the hydroxyl radical is given. The applicability of the TiO2-assisted photocatalytic degradation of C2H5NH2 and (C2H5)2NH was tested at the pilot plant-scale with real solar radiation. The degradation rates and products obtained were similar to those found in the laboratory experiments.

Purpose: In septic shock, myocardial dysfunction develops over the course of illness, but the mechanism of this depression is not clear. In this study, mechanisms of myocardial dysfunction were examined in a porcine model of Escherichia coli sepsis., Materials and Methods: Animals were subjected to 4 hours of bacteria infusion (n = 5) (septic group) or saline infusion (n = 5) (nonseptic group), after which trabeculae were removed from the right ventricle and placed into a recirculating water bath. Measurements of steady-state contraction (SSC) were obtained at 0.5, 1, and 2 Hz. Indirect indices were used to assess abnormalities in myocardial calcium metabolism in sepsis. Extrasystoles (ES) were used to assess transsarcolemmal (TSL) calcium flux and were measured at 300 milliseconds, 400 milliseconds, and 500 milliseconds after the preceding stimulus. Postrest contraction (PRC) is an indicator of SR recirculation from the uptake to the release site and was obtained after interposing intervals of rest between steady-state beats at 0.5 Hz. Rapid-cooling contracture (RCC) is an indicator of sarcoplasmic reticulum (SR) content and was obtained at 0.5, 1, and 2 Hz and after interposing intervals of rest at 0.5 Hz., Results: SSC was not different between groups at 0.5 Hz, but compared with the nonseptic group, SSC decreased at 1 and 2 Hz in the septic group (P < .05). PRC and TSL were not different between groups. During rest intervals, calcium leaks out of SR through the ryanodine channel (ie, SR calcium release channel). In the septic group, as assessed by RCC, SR calcium leak was less than that found in the nonseptic group., Conclusion: These results indicate that myocardial dysfunction in sepsis is frequency dependent, and that the mechanism is most likely caused by inhibition of SR calcium release owing to blockade of the ryanodine channel.

Objective: Polycystic ovary syndrome (PCOS) is associated with higher prevalence of cardiovascular risk factors but the relative prevalence of cardiovascular disease in women with PCOS has not previously been reported. We have compared cardiovascular mortality and morbidity in middle-aged women previously diagnosed with PCOS and age-matched control women., Design: A retrospective cohort study of women diagnosed with PCOS in the United Kingdom before 1979., Patients: Seventy cohort members died before 31 March 1999. Morbidity data were collected from 319 women with PCOS and 1060 age-matched control women. Sixty-one women with PCOS and 63 control women attended a clinical examination., Measurements: Data were collected from death certificates, general practitioners' records and questionnaires with measurement of cardiovascular risk factors in a subsample of questionnaire respondents., Results: All-cause and cardiovascular mortality in the cohort were similar to women in the general population (standardized mortality ratios (95% CI): 93 (72-117) and 78 (45-124), respectively). Women with PCOS had higher levels of several cardiovascular risk factors: diabetes (P = 0.002) hypertension (P = 0.04), hypercholesterolaemia (P < 0.001), hypertriglyceridaemia (P = 0.02) and increased waist:hip ratio (P = 0.004). After adjustment for BMI, odds ratios (OR) were 2.2 (0.9-5. 2) for diabetes, 1.4 (0.9-2.0) for hypertension and 3.2 (1.7-6.0) for hypercholesterolaemia. A history of coronary heart disease (CHD) was not significantly more common in women with PCOS (crude OR (95%CI) 1.5 (0.7-2.9)) but the crude OR for cerebrovascular disease was 2.8 (1.1-7.1)., Conclusion: At long-term follow-up, a history of nonfatal cerebrovascular disease and cardiovascular risk factors including diabetes are more prevalent among women with polycystic ovary syndrome. Morbidity and mortality from of coronary heart disease among women with polycystic ovary syndrome is not as high as previously predicted. This finding challenges our understanding of the aetiology of coronary heart disease in women.

The structures of three new compounds isolated from Peperomia proctorii, named proctoriones A-C, have been established by spectroscopic and chemical methods as 2,3-dihydro-5, 8-dihydroxy-2-pentadecyl-4H-benzopyran-4-one (1) and enolic forms of 4-hydroxy-2-octadecanoylcyclohexane-1,3-dione (2) and 4-hydroxy-2-octadec-(11Z)-enoylcyclohexane-1,3-dione (3).

In septic shock, the extent to which lactic acidosis (LA) is a consequence of splanchnic lactate overproduction (SLP) or impaired hepatic lactate extraction (HLE) is not clear. We examined SLP and HLE in E. coli sepsis in dogs. We further determined the effects of vasopressor treatments, which included phenylephrine, dopamine, norepinephrine, and a combination of dobutamine and norepinephrine treatment, on SLP and HLE in respective groups. The animals were studied while anesthetized and ventilated. During sepsis, SLP increased as compared with presepsis (-0.017 versus 0.07 mmol/min, p < 0.05), but this increase could not be explained by reduced splanchnic oxygen delivery (SOD). During sepsis, HLE increased as compared with baseline (0.8 versus 8%, p < 0.05), but was significantly lower than that found during lactic acid loading in nonseptic dogs. None of the vasopressor treatments had a detrimental effect on SLP. These results indicate that LA in sepsis occurs secondary to an increase in splanchnic lactate production that is not related to reduced splanchnic oxygen delivery, as well as to a decrease in hepatic lactate extraction. Effects of different vasoactive agents did not alter either splanchnic lactate production or hepatic lactate extraction in this sepsis model.